Exocrine pancreas disease affects over 250,000 individuals in the U.S. each year, placing significant burden on the healthcare system. The major exocrine pathologies (pancreatitis, pancreatic cancer) initiate from damaged acinar cells that dedifferentiate to a progenitor cell state. In some cases, the damaged cells can regenerate and undergo a redifferentiation/maturation process that establishes organ recovery. Although acinar cell regeneration has been documented, the transcriptional pathways that control regeneration and differentiation responses are poorly understood. To exploit these regulatory pathways for possible therapeutic strategies will require new and innovative approaches that better define acinar cell biology. The long-term goals of this study are to identify the transcripton networks that govern acinar cell function in healthy and in regenerating adult organs. The objective is to determine how acinar and progenitor transcription factors influence acinar cell regeneration and differentiation events. Our central hypothesis is that misregulation of these transcription networks, in response to cell damage, leads to cell dedifferentiation, cell expansion and redifferentiation back to a healthy acinar cell state. This hypothesis will be tested by pursuing two Specific Aims - (1) identify how acinar and progenitor transcription factors control acinar regeneration events during organ injury and (2) establish how the acinar-specific transcription factor MIST1 directs exocrine function in healthy and diseased cells. The goals of these complementary aims will be accomplished using genetically engineered mouse models that permit gain-of-function and loss-of-function strategies to study the regulatory networks involved in acinar cell regeneration and differentiation. The rationale for the proposed research is that these approaches will be the first to examine how specific acinar and progenitor transcription pathways interface to drive tissue repair upon pancreatic injury. This contribution i significant because it will (i) define epigenetic changes in key regulatory genes during injury and recovery, (ii) test if progenitor pathways are essential to producing a proliferative cell populatin, (iii) identify intracellular pathways by which MIST1 induces acinar cell maturation events, and (iv) establish if these pathways are misregulated in patient samples. The proposed research is innovative because it represents a new and substantial departure from the status quo, by approaching acinar cell replacement from both a dedifferentiation and acinar maturation pathway. The discoveries made will greatly advance the current knowledge of the events associated with acinar cell recovery and are expected to drive future efforts in developing new strategies to harness the regenerative capabilities of acinar cells for remodeling the exocrine and endocrine pancreas. These discoveries will have an important positive impact because defining the biological processes involved in acinar cell homeostasis will provide new opportunities for more effective therapeutics against pancreatic disease.